Respiratory and gastrointestinal dysfunctions associated with auriculo-condylar syndrome and a homozygous PLCB4 loss-of-function mutation

Auriculo-Condylar Syndrome (ACS) is a craniofacial malformation syndrome characterized by external ear anomalies, hypoplasia of the mandibular condyle, temporomandibular joint abnormalities, micrognathia, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The clinical diagnosis is usually suggested by the pathognomonic ear appearance ("question mark ear"), consisting of a variable degree of clefting between the helix and earlobe. The genetic mechanisms underlying ACS have recently been identified. Both autosomal dominant and recessive inheritance of mutations in phospholipase C, beta 4 (PLCB4) and endothelin 1 (EDN1) have been reported along with autosomal dominant mutations in guanine nucleotide-binding protein (G protein) α inhibiting activity polypeptide 3 (GNAI3). We report 6 years of follow-up of a child with a clinical phenotype consistent with ACS due to a homozygous frameshift mutation in PLCB4. The baby presented feeding difficulties associated with failure to thrive and a complex sleep-related respiratory disorder, characterized by central and obstructive apnoeas. Our observations of this case further delineate the phenotype of ACS associated with autosomal recessive PLCB4 loss-of-function mutations, underscoring gastrointestinal dysfunction and severe sleep-related breathing abnormalities as additional features when compared to patients with heterozygous mutations with a presumed dominant negative effect.